The field of organic chemistry continues to seek more efficient and environmentally friendly methods for chemical synthesis. For this reason, tandem reactions have gained wide acceptance in organic synthesis because they assemble complex molecules in a minimum number of laboratory operations and decrease the quantities of chemicals and solvents used. Furthermore, they frequently permit efficient access to unique chemical structures and occasionally result in greater reaction selectivity. A study is proposed to develop and optimize new methodology for the chemical synthesis of compounds having potential in the treatment of a variety of human health problems. The investigation will focus on tandem reaction processes terminating in a Michael addition to an activated alkene. Results from our laboratory have demonstrated the feasibility of simple variations of these reactions for the preparation of carbocyclic structures. The current proposal details the use of more elaborate S(N)2- Michael-Michael, ester cleavage-Michael-Michael, dealkoxycarbonylation- Michael addition sequences for the synthesis of simple, spiro and fused carbocyclic and heterocyclic systems having potential value as medicinal agents. Beyond designing cyclization substrates and optimizing reaction conditions, structure elucidation studies, asymmetric induction studies, and studies exploring methods to develop more efficient and environmentally benign procedures will be undertaken. The benefits of the study will be: (1) to advance our knowledge of organic reactions and reaction selectivities, (2) to develop monk efficient syntheses by exploiting differences in reaction rates such that multistep processes can be performed in a single operation with greater atom economy and reduced environmental impact, (3) to improve the versatility of synthetic approaches to carbocyclic and heterocyclic structures common to established drug compounds or to natural products which have demonstrated biological activity, (4) to develop chemical and enzyme-mediated methods for inducing asymmetry in the cyclization processes, and (5), through agreements with DowElanco and the NCI, to screen the compounds prepared for utility in the treatment of human health disorders. Structure-activity relationships will be explored for compounds which show promise.